The introduction of targeted therapy promised personalized and efficacious cancer treatments. However, although some targeted therapies have undoubtedly improved prognosis and outcome for specific cancer patients, the recurrent problem of therapeutic resistance subdues present revolutionary claims in this field. The plasticity of tumor cells leads to the development of drug resistance by distinct mechanisms:(1) mutations in the target,(2) reactivation of the targeted pathway,(3) hyperactivation of alternative pathways and (4) cross-talk with the microenvironment. Moreover, the intra-tumor heterogeneity of most tumors can also limit therapeutic response. Interestingly, the early identification of some mechanisms of resistance led to the use of alternative agents that improved clinical benefit, demonstrating that an understanding of the molecular mechanisms driving resistance to specific therapies is of paramount importance. Here we review the most generalized mechanisms of resistance to targeted therapies, together with some experimental strategies employed to identify such mechanisms. Therapeutic failure is not an option and we need to understand the dynamics of tumor adaptation in order to adequately adjust therapies; in essence ‘to fight fire with fire’.